Try a new search

Format these results:

Searched for:

in-biosketch:yes

person:schmia1000

Total Results:

436


[S.l]] : Machine Learning in Healthcare Workshop, NPIS 2013

Early Detection of Diabetes from Health Claims

Krishnan, Rahul G; Razavian, Narges; Choi, Youngduck; Blecker, Saul; Schmidt, Ann Marie; Sontag, David
(Website)
CID: 4662682

Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling

Rai, Vivek; Toure, Fatouma; Chitayat, Seth; Pei, Renjun; Song, Fei; Li, Qing; Zhang, Jinghua; Rosario, Rosa; Ramasamy, Ravichandran; Chazin, Walter J; Schmidt, Ann Marie
The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
PMCID:3526353
PMID: 23209312
ISSN: 0022-1007
CID: 203922

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

Ladiwala, Ali Reza A; Bhattacharya, Moumita; Perchiacca, Joseph M; Cao, Ping; Raleigh, Daniel P; Abedini, Andisheh; Schmidt, Ann Marie; Varkey, Jobin; Langen, Ralf; Tessier, Peter M
Antibodies hold significant potential for inhibiting toxic protein aggregation associated with conformational disorders such as Alzheimer's and Huntington's diseases. However, near-stoichiometric antibody concentrations are typically required to completely inhibit protein aggregation. We posited that the molecular interactions mediating amyloid fibril formation could be harnessed to generate antibodies with potent antiaggregation. Here we report that grafting small amyloidogenic peptides (6-10 residues) into the complementarity-determining regions of a single-domain (V(H)) antibody yields potent domain antibody inhibitors of amyloid formation. Grafted AMyloid-Motif AntiBODIES (gammabodies) presenting hydrophobic peptides from Abeta (Alzheimer's disease), alpha-Synuclein (Parkinson's disease), and islet amyloid polypeptide (type 2 diabetes) inhibit fibril assembly of each corresponding polypeptide at low substoichiometric concentrations (1:10 gammabody:monomer molar ratio). In contrast, sequence- and conformation-specific antibodies that were obtained via immunization are unable to prevent fibrillization at the same substoichiometric concentrations. Gammabodies prevent amyloid formation by converting monomers and/or fibrillar intermediates into small complexes that are unstructured and benign. We expect that our antibody design approach-which eliminates the need for immunization or screening to identify sequence-specific domain antibody inhibitors-can be readily extended to generate potent aggregation inhibitors of other amyloidogenic polypeptides linked to human disease.
PMCID:3523860
PMID: 23161913
ISSN: 0027-8424
CID: 205512

The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes

Ramasamy, Ravichandran; Yan, Shi Fang; Schmidt, Ann Marie
The multi-ligand receptor RAGE was discovered on account of its ability to bind and transduce the cell stress-provoking signals of advanced glycation endproducts (AGEs). The finding that RAGE also bound pro-inflammatory molecules set the stage for linking RAGE and inflammation to the pathogenesis of diabetic macro- and microvascular complications. In this review, we focus on the roles of RAGE and its ligands in diabetes complications. We recount the findings from mice, rats, swine and human subjects suggesting that RAGE action potently contributes to vascular, inflammatory and end-organ stress and damage in types 1 and 2 diabetes. We detail the efforts to track ligands and RAGE in human subjects with diabetes to address if this axis may be a biomarker reflective of the state of the diabetic complications. Lastly, we suggest specific strategies to tackle AGE-ligand-RAGE interactions as potential therapeutic targets for diabetes and its complications.
PMCID:3433629
PMID: 22750165
ISSN: 1537-1891
CID: 178279

Aldose reductase, oxidative stress and diabetic cardiovascular complications

Vedantham, Srinivasan; Ananthakrishnan, Radha; Schmidt, Ann Marie; Ramasamy, Ravichandran
Cardiovascular disease represents the major cause of morbidity and mortality in patients with diabetes mellitus. Studies by us and others have implicated increased flux via aldose reductase (AR) as a key player in mediating diabetic complications, including cardiovascular complications. Data suggest that increased flux via AR in diabetics perpetuates increased injury after myocardial infarction, accelerates atherosclerotic lesion formation, and promotes restenosis via multiple mechanisms. Most importantly, studies have shown that increased generation of reactive oxygen species due to flux via AR has been a common feature in animal models of diabetic cardiovascular disease. Taken together, these considerations place AR in the center of biochemical and molecular stresses that characterize the cardiovascular complications of diabetes. Stopping AR-dependent signaling may hold the key to interrupting cycles of cellular perturbation and tissue damage in diabetic cardiovascular complications.
PMCID:3629910
PMID: 22632267
ISSN: 1871-5257
CID: 174070

S100P-Derived RAGE Antagonistic Peptide Reduces Tumor Growth and Metastasis

Arumugam, Thiruvengadam; Ramachandran, Vijaya; Gomez, Sobeyda B; Schmidt, Ann M; Logsdon, Craig D
PURPOSE: The receptor for advanced glycation end products (RAGE) contributes to multiple pathologies, including diabetes, arthritis, neurodegenerative diseases, and cancer. Despite the obvious need, no RAGE inhibitors are in common clinical use. Therefore, we developed a novel small RAGE antagonist peptide (RAP) that blocks activation by multiple ligands. EXPERIMENTAL DESIGN: RAGE and its ligands were visualized by immunohistochemical analysis of human pancreatic tissues, and siRNA was used to analyze their functions. Interactions between RAGE and S100P, S100A4, and HMGB-1 were measured by ELISA. Three S100P-derived small antagonistic peptides were designed, synthesized, and tested for inhibition of RAGE binding. The effects of the peptide blockers on NFkappaB-luciferase reporter activity was used to assess effects on RAGE-mediated signaling. The most effective peptide was tested on glioma and pancreatic ductal adenocarcinoma (PDAC) models. RESULTS: Immunohistochemical analysis confirmed the expression of RAGE and its ligands S100P, S100A4, and HMGB-1 in human PDAC. siRNA silencing of RAGE or its ligands reduced the growth and migration of PDAC cells in vitro. The most effective RAP inhibited the interaction of S100P, S100A4, and HMGB-1 with RAGE at micromolar concentrations. RAP also reduced the ability of the ligands to stimulate RAGE activation of NFkappaB in cancer cells in vitro and in vivo. Importantly, systemic in vivo administration of RAP reduced the growth and metastasis of pancreatic tumors and also inhibited glioma tumor growth. CONCLUSION: RAP shows promise as a tool for the investigation of RAGE function and as an in vivo treatment for RAGE-related disorders. Clin Cancer Res; 18(16); 4356-64. (c)2012 AACR.
PMCID:3845828
PMID: 22718861
ISSN: 1078-0432
CID: 174390

Sensitivity of amyloid formation by human islet amyloid polypeptide to mutations at residue 20

Cao, Ping; Tu, Ling-Hsien; Abedini, Andisheh; Levsh, Olesya; Akter, Rehana; Patsalo, Vadim; Schmidt, Ann Marie; Raleigh, Daniel P
Islet amyloid polypeptide (IAPP, amylin) is responsible for amyloid formation in type 2 diabetes and in islet cell transplants. The only known natural mutation found in mature human IAPP is a Ser20-to-Gly missense mutation, found with small frequency in Chinese and Japanese populations. The mutation appears to be associated with increased risk of early-onset type 2 diabetes. Early measurements in the presence of organic co-solvents showed that S20G-IAPP formed amyloid more quickly than the wild type. We confirm that the mutant accelerates amyloid formation under a range of conditions including in the absence of co-solvents. Ser20 adopts a normal backbone geometry, and the side chain makes no steric clashes in models of IAPP amyloid fibers, suggesting that the increased rate of amyloid formation by the mutant does not result from the relief of steric incompatibility in the fiber state. Transmission electronic microscopy, circular dichroism, and seeding studies were used to probe the structure of the resulting fibers. The S20G-IAPP peptide is toxic to cultured rat INS-1 (transformed rat insulinoma-1) beta-cells. The sensitivity of amyloid formation to the identity of residue 20 was exploited to design a variant that is much slower to aggregate and that inhibits amyloid formation by wild-type IAPP. An S20K mutant forms amyloid with an 18-fold longer lag phase in homogeneous solution. Thioflavin T binding assays, together with experiments using a p-cyanophenylalanine (p-cyanoPhe) variant of human IAPP, show that the designed S20K mutant inhibits amyloid formation by human IAPP. The experiments illustrate how p-cyanoPhe can be exploited to monitor amyloid formation even in the presence of other amyloidogenic proteins.
PMCID:3388178
PMID: 22206987
ISSN: 0022-2836
CID: 174534

Insulin resistance and metabolic syndrome: mechanisms and consequences

Schmidt, Ann Marie
PMID: 22815339
ISSN: 1079-5642
CID: 174080

Islet amyloid: From fundamental biophysics to mechanisms of cytotoxicity [Meeting Abstract]

Raleigh, Daniel; Abedini, Andisheh; Cao, Ping; Marek, Peter; Meng, Fanling; Middleton, Chris; Patsalo, Vadim; Plesner, Annette; Schmidt, Ann Marie; Tu, Ling-Hsien; Verchere, C. Bruce; Wang, Hui; Zanni, Marty
ISI:000307019800042
ISSN: 0961-8368
CID: 175798

The molecular basis of islet amyloid induced cell death [Meeting Abstract]

Abedini, Andisheh; Plesner, Annette; Cao, Ping; Zhang, Jinghua; Meng, Fanling Meng; Middleton, Chris; Song, Fei; Zanni, Martin; Verchere, C. Bruce; Raleigh, Daniel; Schmidt, Ann Marie
ISI:000307019800378
ISSN: 0961-8368
CID: 175797